Pain is the hallmark of vasocclusion (VOC) in Sickle Cell Disease (SCD). Evidence for a major role for inflammation in VOC is provided by studies demonstrating proinflammatory cytokines such as TNFo, IL1li, leucotrienes (LKTs) and lipid peroxidation products (which are all elevated in SCD) sensitize nociceptors and act as agonists for the TRPV1 and TRPA1 channels which play a role in neural and non neural pain. In children with SCD, an increase in thermal pain sensitivity suggests a further link between nociceptor sensitization and inflammation , with evidence that n-3 PUFA supplementation with Docosahexanoic and Eicosapentanoic acids (DHA and EPA) decrease VOC episodes. However, no systematic analyses of pro and anti-inflammatory biomarkers has been conducted. In addition, DHA and EPA via their lipoxygenase products (Resolvins of D and E series) are potent inhibitors of inflammation and inhibit the TRPV1 and TRPA1 channels. We will conduct a dose escalation Phase l/ll Safety/Efficacy Trial of DHA/EPA (25 and 45mg/kgm) for 6 months in children 9 to 19 years with HbSS and HbS?Thal. We will add new perspectives to the previous Trials conducted in Nigeria and Sudan. Namely (i) evaluate safety of low and a moderately high dosage, (ii) check periodically for Trial compliance by assays of whole blood DHA/EPA, (iii) evaluate effects of n-3 PUFAs on proinflammatory (hsCRP, TNFa, ILIIi, LKTs and lipid peroxidation products) and anti-inflammatory markers (Resolvins RvDI and E1), (iv) test for modulation of thermal pain sensitivity by quantitative sensory testing (to link pain and pain-related eicosanoids and cytokines), (v) assess QoL parameters as a relevant summation of DHA and EPA effects. In an additional Aim, we will assess biobanked plasmas for select biomarkers from a previous longitudinal study of 100 young children with SCD whose pain experiences had been rigorously characterized. Novel statistical modeling approaches will retrospectively identify classes of children based on joint inflammatory biomarker and pain frequency profiles, identifying surrogate markers of pain in SCD. These 2 Aims should set the stage for a future Phase III Trial of n-3 PUFAs in modulating pain and inflammation in SCD.